Acridine compounds and process of making same



Patente d July 5, i949 UNITED STAT ES PATENr OFFICE AiCRIDINE COMPOUNDS iQNlI) E'PBGGESS OF MAKING SAME,

Joseph H. Burckhalter, Detroit, ,Eldon M. Jones. and Albert L. ,Rawlins, ,Grossejllointewoods, Frank H. Tendic'k, Grosse llointe Park, and Walter F. Holcomb, Detroit, Mich., asslgnorsto Parke;.Davis &:Company, Detroit, Mich a poration of Michigan No Drawing. Application November. 19,

Serial No. 629,713

14 Claims. "(01; 260-279) This invention relates to certain new anduseful acridine compounds andimethods Ioriobtaining the same. More particularly, the invention relates to acridine compounds having the formula, I

where R is hydrogen, lower alkoxy or lower alkyl,

R1 ishydrogen, lowernalkoxy or lower alkyl, R2

is hydrogen, halogen or CN, R3 is hydrogen, halogen, lower alkyl, or lower .alkenyLfRafis hydrogen .or an alkyl radical containing Etc .10 carbon atoms inclusive and R5 is an alkyl radical containing 5 to carbon atoms inclusive.

These new compounds are useful therapeutic agents and, in general, they rare oliaracterizedtby These compounds their toxicity to :plasm-odia. may be used either in the form of their bases or their salts with organic or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, lactic acid,

tartaric .acid, sir-iconic wacid, :citric acid and alkyl sulfonic acids or as the insoluble salt of methylene disalicylic acid.

The compounds of the present invention may be prepared by the reaction of a substituted aminophenol of the formula,

with a il-halo :or a -9-a1yloxyacridine :compound of the formula, r r

where R, R1, R2, R3, R4 and R5 have "the same significance as givenabove and X is a chlorine or bromine atom or an aryloxy radical.

The reaction may be carried out by reacting approximately equimolar quantities of the two reactants in a suitable solvent. Such solvents are, in general, water, water-miscible organic solvents and mixtures of water and water-miscible organic solvents. some, of the water-miscible organic solvents which we may use are low molecular alcohols, such; as methanol, ethanol and 'n-propanol, low molecular weight ketones such as actone and methyl ethyl ketone and ethers such as dioxane and ethylene glycol monoethyl ether.

We prefer to carry out the above reaction of the 9-haloacridine compound and the substituted eminophenol in .thepresence of an acidic catalyst. Suchcatalysts are dilute and concentrated onganic acids, phenols and dilute inorganic acids. The inorganicacids which we use are, in general, mineral acids such as hydrochloric, hydrobrom'ic, sulfuric, phosphoric and the like acids. Some of the organic acids which we may use are acetic, propionic, butyric and the like acids. When the reaction is carried-put in the presence of a concentrated organic acidor a phenol, the acid or phenol serves: both as the catalyst and as the solvent. "Some of the phenols which we employ to effect the reaction are ,phenol, o-cresol, p-cresol, m-cresol, mixed cresols and the like.

When a phenol is used as "rthe solvent and. catalyst the Q-halo acridine compound probably reacts with the solvent to form the corresponding intermediate 9-aryloxy acridine compound which then reacts with the substituted aminophenol. Equally satisfactory results may be obtained when using axpheno'l :asasolyent "by starting with the 9-aryloxyacridine compound and :the substi- 2,474,824 3' 4 tuted aminophenol. The transformations involved are represented by the following equations.

HIJ

where R, R1, R2, R3, R4 and Rshave the same The invention is illustrated by the following significance as given above and Hal vrepresents examples.

a chlorine or bromine atom.

A modification of our process for obtainin these new'compounds involves the use of an 25 N-acyl derivative of the substituted'aminophenol.

In this modification the acyl derivative is .1151: drolyzed to the aromatic amine under acidic con- NH OH ditions and the amine so formed caused to react simultaneously or subsequently with the 9-halo- 30 c ,Nwmcmomomcmom), acridine compound. This. is illustrated by the following equations.

Example 1 .-2 -methox 2j-6-chl0ro-9- (3 dz'-n Jzexylaminomethyl 4'-hydroxycmilino) acridine To a solution of 20 g. of Z-di-n-hexylaminomethyl-i-aminophenol dihydrobromide dissolved in 200 m1. of isopropanol 11 g. of 2-methoxy-6,9- dichloroacridine is added and the resultant mixture refluxed for one and a half hours. The solution is cooled, the crystalline dihydrobr-omide salt of 2 methoxy-6-chloro-9-(3'-di-n-hexylaminomethyl-4'-hydroxyanilino) acridine removed by r filtration and purified by recrystallization from methanol-acetone mixture. r

By using an equivalent amount of 2-di-n-hexylaminomethyl 4-aminophenbl dihydrochloride instead of the dihydrobromide salt in this prodl-n-hexylaminomethyl-4'-hydroxyanilino) acridine dihydrochloride.

Example 2.- 2-meth0:cy-6-chloro-9-(3'-di-noctylaminomet-hyZ-4'-hydroa:yanilino) acridine NH-O-OH CHZN CH1CHICHICH2CH2C HaCHzCHr):

40 g. of 2-di-n-octylaminomethyl-4-acetylaminophenol is refluxed for one hour with '75 cc. of 6 N hydrochloric acid. The solution is cooled and made just acid to Congo red by the addition of dilute sodium hydroxide solution. 27 g. of 2- methoxy-6,9-dichloroacridine is added and the 7 mixture refluxed for one and a half hours, cooled where R, R1,'R2, R3, R4, R5 and Hal have the and the crude dihydrochloride of the product same significance as givenabove and Re is a lower which separates removed and purified by recrysalkyl or an aryl radical.

75 tallization from methanol.

cedure, one obtains 2-methoxy-6-chloro-9-(3'- Example 3.--2-methoxy-6-chloro-9-(3'-n-hcryZ- aminomethyt-l -hydro:cyanilmo) acridine CH O 112C HaCHaCHzCHzCHg Example 4.-2,3 dimethoxy 9 (3'-di-n-herylaminomethyl .5'- chloro 6 hydromyanilino) acridine 38.2 g. of 2-chloro--di-n-hexylaminomethylfi-acetylamin'ophenol is heated with "75 cc. of -6 N hydrochloric acid for one hour, the solution cooled and the pH adjusted to about 4 by the addition of 40% sodium hydroxide solution. 27 g. of 2,3-dimethoxy-9-chloroacridine and "75 cc. of 95% ethanol are added and the mixture refluxed for one and a half hours. The mixture is cooled, made alkaline with dilute sodium hydroxide solution and extracted with ether. The combined ether extracts are dried and the ether distilled to obtain the iree base of 2,3-dimethoxy- 9 (3' di n hexylaminomethyl-Ei -:chloro-6-hydroxyanilino) acridine. The base :may be purifled by recrystallization from ethanol or it may be converted to the dihydrochloride salt and purified in this manner. The base. is taken up in an excess of alcoholic hydrogen chloride and the dihydrochloride precipitatedsby the addition of acetone. The crude dihydrochloride which separates is collected and purified by recrystallization from methanol-acetone mixture.

Example 5.9- (3'hydroxy-4"-di-n-heptylaminomethylanilino) ucridine 25.5 g. of 9-bromoacridineis dissolved in 100 g. 01' phenol by heating at 100 C. for thirty minutes. The solution is cooled and 33.4 g. of 2 di n heptylam'inomethyl -.5 aminophenol added. The resulting mixture is heated at 1 00 for three hours with stirring, cooled and diluted with about one liter of water. The mixture is made razlkailine with dilute sodium hydroxide solution and extracted with ether. The ether extracts are washed with*5% sodium hydroxide solution, then with water and dried. The ether is evaporated to obtain the yellow free base of anilino) acridine. The product may be purified by recrystallization .f romisopropanol or isopmpanols-lig-roin mixture.

Example '6.-2.3-dimethylefi-bromo -9- (3'-dimamylaminomethyl 4' hydroxy 6' methyl aniline) acridima ommomomomomom A mixture consisting of 36.5 g. of 2-di--n-amylaminomethyl-4amino-6-methy1phenol dihydrochloride and 32 g. of 2,'3-di-methyl-6-bromo-9- ohloroacridine in 300 cc. of absolute ethanol is reflux-ed for two hours, 'cooled and the crude di'hydrochloride of the product collected. The crude product is purified by recrystallization from methanol.

Example 7.-- 2 methoxy-fi ci /[mo -.9 (3' dz noctylaminomethyl-4'-hydroa:yanilino) acrz'dine 3mm0H1onlomomonlomom'onnI Emample 8,-2 -methoxy-6-bromo-9- (3' -n-hep- :tylqminomethyl 4 hydrowy 5 allylanilz'no) 'acridzne H z :n'mLomonlonlomonzonlonl 31.8 g. of 2-n-hepty1am'inomethyL-4-acetylam-ino-fi-allylphenol is refluxed in 50 cc. of concentrated hydrochloric .acidior one hour. The solution is cooled and made just acid to Congo red by the addition of. sodium hydroxide solution. 32g. of 2-methoxy-6-bromo-9-chloroacridine is added, the mixture r'efiuxedfor one and a half hours, cooled and diluted to a volume 7 of 500 cc. with water. The mixture is made just alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extracts are washed, dried and the chloroform distilled. The gummy residue consists of the free base of 2-methoxy-6-bromo-9-(3'-n-hepty1- aminomethyli'-hydroxy-5allylanilino) acridine. The crude product may be purified by dissolving it in absolute ethanol and adding an excess of alcoholic hydrogen chloride solution. The dihydrochloride salt .is precipitated by the addition of acetone, collected and purified by recrystallization from methanol-acetone mixture.

Example methyl-4-hydroa:yanilin0) acridine where R. is a member of the class consisting of hydrogen, lower alkoxy and lower alkyl radicals, R1.

is a member of the class consisting of hydrogen, lower alkoxy and lower alkyl radicals, R2 is a 9.-2-methyl-9-(3-di-n-decylaminomember of the class consistin of hydrogen, halogen and --CN, R3 is a member of the class con-.

A!HnN(CHaCHzCHzCHaCHzOHgCHzCHaCHrCH A solution of 48.5 g. of Z-di-n-decylaminomethyl-4-acetylaminophenol in 75 cc. of 4 N hydrochloric acid is refluxed for one hour, cooled and made just acid to Congo red by the addition of dilute sodium hydroxide solution. 22.7 g. of 2-methyl-9-chloroacridine is added, the mixture refluxed for one and a half hours and then cooled. The crude dihydrochloride of theproduct is collected and purified by recrystallization from methanol-acetone mixture.

The acid addition salts of the new acridine compounds of the present invention may be prepared by treating an alcoholic solution of the base with an excess of the appropriate organic or inorganic acid. In most instances the acid addition compound separates immediately but, if desired, it may be precipitated by the addition of acetone or ether. These salts may, in general, be purified by recrystallization from methanol, ethanol or methanol-acetone mixture.

The substituted acylaminophenols used as starting materials are usually prepared from the corresponding acylamino-phenols as described in German Patent No. 92,309. The substituted acylaminophenols can be hydrolyzed to the corresponding substituted aminophenols by means of mineral acid or alkali. The meta substituted aminophenols may, as well as the above ortho and para derivatives, be prepared by the catalytic or nascent hydrogen reduction of the corresponding substituted nitrophenols which can be prepared by the Mannich reaction or by the reaction of the chloro or bromo-methylnitrophenols with a primary or secondary amine.

The 9-haloacridine compounds used in the practice of the present invention may be prepared in the conventional manner which involves the condensation of an aromatic amine with an ortho halobenzoic acid followed by simultaneous ring closure and halogenation.

Attention is directed to applicants copending applications Serial No. 539,990, filed June 12, 1944, now Patent No. 2,428,355, issued October 17, 1947, and Serial No. 571,961, filed January 8, 1945, wherein certain acridine compounds somewhat related to the compounds of the instant application are described and claimed.

What we claim as our invention is:

1. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

sisting of hydrogen, halogen, lower alkyl, and lower alkenyl radicals, R4 is a member of the class consisting of hydrogen and alkyl radicals containing 5 to 10 carbon atoms inclusive, R5 is an alkyl radical containing 5 to 10 carbon atoms inclusive, and the group is in one of the positions ortho and para to the -OH group.

2. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

3. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

base and its acid addition salts, said free base having the formula,

NH OH H CHaO HaN GH CH OH OH CH CH; Cl I I N sbempoumaor the tiormulaa T Q amcmcmomomentous, l i -ZHO1 6. A compound of, the formula, NEQOH 1 c 2N(OH2CH2CH2EH20H2CHCH2CH| 1 01 7. A compound of the formula,

8t Process for obtaining. a; compound of the class consisting'of a freebase and its acid addition salts, said free base having the formula,

which comprises reacting a: Q- substituted acridine compound of the formula,

witha substituted aminophenol of the formula,

where X is a member of the class consisting of halogen and aryloxy radicals, R. is a member of the class consisting of hydrogen, lower alkoiqr and lower alkyl radicals, R1 is a member of the class consisting of hydrogen, lower alkoxy and lower alkyl radicals, R2 is a member of the class consisting of hydrogen, halogen and CN, R3 is a member of the class consisting of hydrogen, halogen, lower alkyl, and lower alkenyl radicals, R4 is a member of the class consisting of hydrogen and alkyl radicals containing 5 to 10 carbon atoms inclusive, R5 is an alkyl radical containing 5 to 10 carbon atoms inclusive, and the R4 -OH;N

rm;;isi:in one. oi tha positions ortho and parato the --OH group.

9. Process for obtaining a compound of the class consisting of a free base and its acid addition salts, said freeubase having the formula,

which omprises reacting a; Q-haloacridine com- Wand of thejitbrmnla,

witha substituted"amlnophenol ofjthe formula,

group is in one of the positionsorthn and para to the OH group.

10. Process for obtaining a compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

which comprises reacting a 9-haloacridine compoundof the formula,

in {Malllll with a substituted aminophenol of the formula,

in the presence of; a dilute mineral acid, where X is a halogen atom, R is a member of the class consistin of hydrogen, lower alkoxy and lower alkyl radicals, R1 is a member of. the class consisting of hydrogen, lower'alkoxy and lower alkyl radicals, R2 is a member of the class consisting of hydrogen, halogen and -CN, R3 is a member of the class consisting of 'hydrogemhalogen, lower alkyl, and lower alkenyl radicals, R4 is a member of'th'e class consisting of hydrogen and alkyl radicals containing 5 to 10 carbon atoms inclusive, R5 is an alkyl radical containing 5 to 10 carbon atoms inclusive, and the '7 -CH N o RB group is in one of the position ortho and para to the --OI-I group.

11. Process for obtainin a compound of the class consisting of a freebase and its acid addition salts, said free basehaving the formula,

which comprises reacting 2 methoxy- 6,9 dichloroacridine with Z-di-n-hexylaminomethyle iaminophenol. I

12. Process for obtaining acompound oi": the class consisting of a free base and its acid addition salts, said free base having the formula,

CHsO

oir 'N omomomomomcmemoirs),

which comprises reacting 2 methoxy 6,9 -'dl- *chloroacridine with 2-di-n-octylaminomethyl-4- 7 aminophenol.

13. Process for obtaining a compound of the class consisting of a free base and'lts acid addition salts, saidfree base having the formula,

CHsCHzCEhCHzCHgCEh which comprises reacting 2 methoxy 6,9 dichloroacridine with 2-n-hexy1aminomethyl-4- aminophenol. V e

14. An acid addition salt of a free base, said free base having the formula,

where R is a member of the class consisting of hydrogen, lower alkoxy and lower alkyl radicals, R1

is a member of the class consistin of hydrogen,

lower alkoxy and lower alkyl radicals, R2 is a member of the class consisting of hydrogen, halogen and CN, R3 is a member of the class consisting of hydrogen, halogen, lower alkyl and lower alkenyl radicals, R4 is a member of the class consisting of hydrogen and alkyl radicals containing 5 to 10 carbonatoms inclusive and R5 is an alkyl radical containing 5 to 10 carbon atoms inclusive.

JOSEPH H. BURCKHALTER.

ELDON M. JONES.

" ALBERT L. RAWLINS.

FRANK H. TENDICK. WALTER F. HOLCOMB.

No references cited 

